Substance abuse is one of the most pressing medical and social issues today. We have previously demonstrated that a single dose of cocaine results in a long-term change in the synaptic strength of the midbrain dopamine neurons. We have now shown that all classes of addictive drugs have a similar effect despite diverse primary mechanisms of action. This proposal is aimed at investigating the mechanisms and the behavioral implications underlying this effect. Specifically, I will ask whether the mechanisms are congruent with the general mechanisms of long-term potentiation as described in the hippocampal literature. I will use a number of tools and paradigms to address this question. GluRI AMPA subtype receptors and calmodulin-dependent protein kinase II (CaMKII) have been shown to be required for LTP. I will use mice that have knockout and diminished function mutations to ask if the mid-brain dopamine cell's response to cocaine also depends on these proteins. I will also develop and use a novel peptide reagent to deliver a CaMKII inhibitor to the brain in vivo to confirm the mutant mouse data. I will define the monoamine receptor(s) required for the cocaine effect using in vivo antagonists. I will also use virally-mediated expression to test if the synaptic enhancement in dopamine cells uses the dynamic machinery for regulating synaptic AMPA receptors as it does in the hippocampus. These studies will help define the relevant parameters for establishing a behavioral correlate to the cocaine effect. Robert Malenka MD PhD will be my primary mentor for this project. He has over twenty years of research experience on the cutting edge of science. He has successfully mentored numerous postdoctoral fellows and K08 recipients. In the long term, I intend to run an independent laboratory in a psychiatry department. I will spend 80 to 90% of my time looking at the physiological processes involved in addiction and using well-defined behavioral models to examine the in vivo effects of molecular manipulations that derive from the physiology. My goal will be to define the molecular players in the addictive process and eventually to find molecular targets for intervention. I will spend ten to twenty percent of my time seeing patients with students and residents in a psychiatry clinic. Designing and carrying out this proposal will clearly prepare me to meet my professional goals.